Antibiotic resistance is currently one of the most significant public health concerns. The World Health Organ- ization recently identified antimicrobial resistance as one of the three greatest threats facing mankind in the 21st century. Cationic host-defense peptides (HDPs) are small cationic amphiphilic peptides, and are an an- cient and vital part of the innate immune system. However, HDPs have significant drawbacks such as suscep- tibility to enzymatic degradation, low-to-moderate activity and their inconvenient optimization. We have recently developed a new class of sequence-specific peptidomimetics termed ??-AApeptides?. In ad- dition to their intrinsic advantages including enhanced stability against proteolysis and limitless potential for chemical modification, some potent molecules display broad-spectrum antimicrobial activity, and do not induce apparent resistance in drug-resistant pathogens. Furthermore, they can also modulate immune responses and show strong anti-inflammatory activity. In addition, one lead compound has shown potent in vivo activity against MRSA in mouse model. Our preliminary data suggest that antimicrobial ?-AApeptides mimic the global structure, function and mechanism of AMPs. These findings strongly suggest ?-AApeptides may be a new ap- proach for antibiotic development. The objective here, is to synthesize, develop and evaluation of more potent analogs of previously designed antimicrobial cyclic-lipidated ?-AApeptides. We will design and synthesize nov- el analogs of previously designed antimicrobial cyclic-lipidated ?-AApeptides, including cyclic-lipidated ?- AApeptides with different length of alkyl tails, diverse cationic and hydrophobic groups and expansion of cyclic- lipidated ?-AApeptides to new classes of cyclic-lipidated peptidomimetics with novel backbones. All the pep- tides need to be analyzed and purified by HPLC. Thus, a HPLC equipped with both analytical and preparative modules (Waters 1525EF) extremely critical for our proposed research.